Aminoalkyl-sp irocycloalkanes

ABSTRACT

1-Basically substituted benzcycloalkane-2-spirocycloaliphatic compounds, e.g. those of the formula   A aminoalkyl or N-alkyl-(azacycloalkyl or azacycloalkyl-alkyl) R H or OH m 1-3 B alkylene or alkenylene ACYL OR 1-DEHYDRO DERIVATIVES, N-oxides, quaternaries or salts thereof exhibit analgetic effects.

United States Patent [191 Werner AM lNOALKYL-SP IROCYCLOALKANES [75] Inventor: Lincoln Harvey Werner, Summit,

[21] Appl. N0.: 179,565

Related U.S. Application Data [63] Continuation-impart of Ser. No. 796,166, Feb. 3, 1969, Pat. No. 3,706,756, which is a continuation-in-part of Ser. No, 723,585, April 23, 1968, Pat. No. 3,657,440.

[52] U.S. Cl. 260/295.5 S; 260/239 A; 260/562 R; 260/239 B; 260/567.5; 260/239 R; 260/567.6

M; 260/240 R; 260/570.8 R; 260/243 B;

B; 260/612 R; 260/247.7 A; 260/618 F;

260/645; 260/268 R; 260/665 G; 260/268 C; 260/244; 260/293; 260/246; 260/294.3;

260/330; 260/456 R; 260/456 P; 260/465 F; 260/479 R; 260/490; 260/501.11;

[51] Int. Cl. C07c 87/28 [58] Field of Search... 260/570.8 R, 501.21, 501.12, 260/501.18, 501.19, 295.5; 424/330 [451 June 17, 1975 [56] References Cited UNITED STATES PATENTS 3,706,756 12/1972 Werner 260/295.5

Primary ExaminerR. V. Hines Attorney, Agent, or Firm-loseph G. Kolodny; John J. Maitner; Theodore O. Groeger [57] ABSTRACT l-Basicz lly substituted benzcycloalkane-Z- spirocycloaliphatic compounds, e.g. those of the formula \CCB CH 5 Claims, No Drawings ll AMllNOALKYlL-SP IROCYCLOALKANES CROSS-REFERENCES TO RELATED APPLICATIONS This is a'continuation-in-part of application Ser. No. 796,166, filed Feb. 3, 1969 (now US. Pat. No. 3,706,756), which in turn is a continuation-in-part of application Ser. No, 723,585, filed Apr. 23, 1968 (now US. Pat. No. 3,657,440).

SUMMARY OF THE INVENTION The present invention concerns and has for its object the provision of new l-basically substituted benzcycloalkane-2-spriocycloaliphatic compounds, preferably of those corresponding to Formula I in which Ph is a 1,2-phenylene radical, alk, is lower alkylene contributing l to 3 ring-carbon atoms, B is lower alkylene or alkenylene contributing 4 to 6 ring carbon atoms, A is amino-lower alkyl or N-lower alkyl- (lower azacycloalkyl or azacycloalkyl-lower alkyl) and R is hydrogen or hydroxy, of the l-dehydro derivative Noxide, acyl derivatives, quaternaries or salts thereof, as well as of corresponding pharmaceutical compositions and of methods for the preparation and application of these products, which are especially useful analgetic agents.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The 1,2phenylene radical Ph is unsubstituted or substituted by one or more than one, preferably up to two, of the same or of different substituents attached to any of the four positions available for substitution. Such substituents are primarily lower alkyl, e.g. methyl, ethyl, nor i-propyl or -butyl, free, etherified or esterifled hydroxy, such as lower alkoxy, e.g. methoxy, ethoxy, nor i-propoxy or -butoxy, lower alkanoyloxy, e.g. acetoxy or propionyloxy, or halogeno, e.g. fluoro, chloro or bromo, trifluoromethyl, nitro or amino, especially di-lower alkylamino, e.g. dimethylamino or diethylamino, The term lower referred to above or hereinafter in connection with organic radicals or compounds respectively, defines such with up to 7, preferably up to 4, carbon atoms. More particularly Ph stands for 1,2- phenylene, (lower alkyl)-l,2-phenylene, (hydroxy)- 1,2-phenylene, monoor di-(lower alkoxy)-I ,2

phenylene, (lower alkanoyloxy l ,2-phenylene, (halogeno)-l,2-phenylene or (trifluoromethyl)-I,2- phenylene.

The lower alkylene portion alk above all represents methylene, 1,2-ethylene or 1,3-propylene, but also represents l,l-ethylene, 1,1-, 1,2- or 2,2-propylene, 2-methyll,3-propylene, 1,1-, 1,2-, 1,3-, 2,2- or 2,3- butylene, 1,1-, 1,2-, 1,3-, 2,2-, 2,3, 2,4- or 3,3 pentylene, 1,3- or 2,3-hexylene or 3,5-heptylene.

The lower alkylene or alkenylene radical B preferably represents 1,4-butylene, 1,5-pentylene, 1,6-

hexylene or l,5-pent-2-enylene, but also represents 1,4-pentylene, 1,4-, 1,5- or 2,5-hexylene, 1,4-, 1.5-, 1,6-, 2,5- or 2,6heptylene; 1,4-but-2-enylene, 1,4- pent-Z-enylene, l,6-hex-3-enylene or 2,6-hep-3- enylene.

An amino-lower alkyl group A is represented by Amalk wherein the lower alkylene radical alk above all stands for 1,2-ethylene, 1,2- or l,3-propylene, but also for 2-methyl-l,3-propylene, 1,2-, 1,3-, 1,4- or 2,3- butylene, 1,5- or 2,4-pentylene, 1,3-, 1,4- or 1,6- hexylene or 3,5heptylene.

The amino group Am is a primary, secondary or preferably a tertiary amino group, such as amino, monoor di-lower alkylamino, e.g. methylamino, ethylamino, nor i-propylamino or n-butylamino; dimethylamino, N- methyl-N-ethylamino, diethylamino, di-n-propylamino, di-isopropylamino or di-n-butylamino; free or esterified hydroxy-lower alkylamino, N-(hydroxy-lower alkyl)-N- lower alkylamino or di-(hydroxy-lower alkyl)-amin0, in which hydroxy is separated from the amino nitrogen by at least 2 carbon atoms, e.g. 2-hydroxyethylamino, 3- hydroxypropylamino, N(2-hydroxyethyl)-N- methylamino or di-(Z-hydroxyethyl)-amino; monocyclic lower cycloalkylamino, cycloalkyl-Iower alkylamino, N-cycloalkyl-N-lower alkylamino or N- cycloalkyl-lower alkyl-N-lower alkylamino in which cycloalkyl has preferably 3 to 7 ring-carbon atoms, e.g. cyclopropylamino, cyclopentylamino, cyclohexylamino, cyclopropylmethylamino, 2-cyclopentylethylamino, N-cyclopentyl-N-methylamino, N- cyclohexyl-N-methylamino, N-cyclohexyl-N- ethylamino, N-cyclopentylmethyl-N-ethylamino or N- (2-cyclopentylethyl)-N-methylamino, aralkylamino or N-lower alkyl-N-aralkylamino, in which the aryl, e.g. phenyl, moiety is unsubstituted or substituted as shown for Ph above, such as benzylamino, Z-phenethylamino, N-methyl-N-benzylamino, N-ethyl-N-benzylamino or Nethyl-N-( lor 2-phenethyl)-amino; lower alkyleneimino or free or esterified hydroxyalkylcneimino, e.g. ethyleneimino, pyrrolidino, 2- rnethyl-pyrrolidino, piperidino, 2- or 4-methylpiperidino, 3- or 4-hydroxy-piperidino, 3- hydroxymethyl-piperidino, I ,6 or 2,5- hexamethyleneimino, 1,7- or 2,6- heptamethyleneimino, lower mono-oxaor thiaalkyleneimino, e.g. morpholino, 3-methyl-morpholino or thiamorpholino, monoazalower alkyleneimino, N- lower alkylor free or esterified N-(hydroxy-lower alkyl)-monoaza-lower alkyleneimino, e.g. piperazino, N- (methyl, ethyl, n-propyl, i-propyl, 2-hydroxyethyl or 3-hydroxypropyl)-piperazino, N(methyl, Z-hydroxyethyl or n-propyl)-3-aza-1,5- or 1,6-hexyleneimino, or N-methyl4-a2a-1,7 or 2,6-heptyleneimino.

The amino group Am may also be linked with the alk moiety, so that A represents N-lower alkyl-monoazalower cycloalkyl or N-lower alkyl-monoaza-lower cycloalkyl-lower alkyl, e.g. l-(methyl or ethyl)-3- pyrrolidyl or -pyrrolidylmethyl, l-(methyl or ethyl)-3- or 4-piperidyl or -piperidylrnethyl. In the corresponding compounds of Formula I, the heteroatoms in the saturated moieties, e.g. those present in Am, are separated from each other by at least 2 carbon atoms.

Acyl derivatives of the invention are preferably those of the primary or secondary amines or hydroxyalkyl compounds. The acyl group therein stands preferably for lower alkanoyl, such as acetyl, propionyl, butyryl or pivalyl, but also for lower alkenoyl, such as acryloyl or methacryloyl, monocyclic carhocyclic aryl-lower all anoyl or -alkenoyl, such as benzoyl, phenylacetyl or cinnamoyl. The quaternaries of the invention are preferably the lower alkyl or aralkyl, e.g. phenyl-lower alkyl quaternaries. Said acyl, alkyl or aralkyl radicals are unsubstituted or substituted, especially in the aromatic portion, as shown for Ph above.

Dehydration of the compounds of Formula I, wherein R is hydroxy, yields the l-dehydro derivatives of the invention, in which the double bond can only extend into A, thus rendering, for example, alk to the correspond ing alkylidene radical.

The compounds of the invention exhibit valuable pharmacological properties. For example, they show analgesic activity as can be demonstrated in animal tests, using advantageously mammals, such as rats, mice, or rabbits as test objects. Such tests can be performed as follows: A radiant heat stimulus is applied to the tail of male mice and the duration of exposure is measured. The end-point is the time at which the animal moves its tail away from the stimulus, which never is applied longer than seconds. Usually ten mice are used for each test and two pre-drug time values are obtained from each animal. I-lereupon the compounds of the invention are orally or subcutaneously applied in the form of aqueous solutions or suspensions, for example, in the dosage range between about 1 and 200 mg/kg/day, preferably between about 10 and 100 mg/kg/day, and 15, 3O and/or 60 minutes thereafter two post-drug time values are obtained. To determine the presence of an analgesic effect, the control mean is determined and 3 standard deviations are added; any value above said sum is considered a reactor value, i.e. such indicating analgesia.

In another test system, about l mm holes are drilled to the dental pulp of 2 incisor teeth of anesthetized male rabbits. The following day electrodes are inserted into said holes and a current of about 6 V is applied to the unanesthetized animal, at which value it usually starts licking, thus providing the control voltage values. Hereupon the compounds of the invention are applied as mentioned above in about the same dosage range and about minutes thereafter again a current is applied until the animal starts licking. In case the voltage ranges above 6 and up to 14 V, analgesia is observed. Accordingly, the compounds of the invention are useful analgetic agents. They are also useful intermediates in the preparation of other valuable compounds, especially of pharmacologically active products.

Particularly useful are compounds of the Formula I, in which Ph is unsubstituted 1,2-phenylene or 1,2- phenylene substituted by up to two members selected from the group of lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogeno, trifluoromethyl, nitro, amino or di-lower alkylamino, alk, is lower alkylene contributing 1 to 3 ring-carbon atoms, B is lower alkylene or alkenylene contributing 4 to 6 ring-carbon atoms, A is [amino, mono or di-lower alkylamino, N- (hydroxy-lower alkyl)-N-lower alkylamino, di- (hydroxy-lower alkyl)-amino in which hydroxy is separated from amino by at least 2 carbon atoms, monocyclic lower cycloalkylamino, cycloalkyl-lower alkylamino, N-cycloalkyLN-lower alkylamino or N- cycloalkyl-lower alkyl-Nlower alkylamino, I-lPh-lower alkylamino, N-lower alkyl-HPh-lower alkylamino, lower alkyleneimino, hydroxy-lower alkyleneimino, lower mono-(oxa, thia or aza)-alkyleneimino or N- (lower alkyl or hydroxy-lower alkyl)-monoaza-lower alkyleneiminol-lower alkyl, N-lower alkyl-monoazalower cycloalkyl or N-lower alkyl-monoaza-lower cycloalkyl-lower alkyl wherein the heteroatoms in the saturated moieties are separated from each other by at least 2 carbon atoms and R is hydrogen or hydroxy, or the ldehydro derivative thereof, a lower alkanoyl, lower alkenoyl, HPh'lower alkanoyl or I-IPh-lower alkenoyl derivative of the primary or secondary amino or hydroxyalkyl compounds, the N-oxide or lower alkyl or HPh-lower alkyl quaternaries of the tertiary amino compounds or therapeutically useful acid addition salts thereof.

Preferred compounds of Formula I are those in which Ph is 1,2-phenylene, (lower alkyl)-l,2-phenylene, (hydroxy)-l,2-phenylene, monoor di-(lower alkoxy)- l,2-phenylene, (lower alkanoyloxy)-1,2-phenylene, (halogeno)-l,2-phenylene or (trifluoromethyl)-1,2- phenylene, alk is methylene, 1,2ethylene or 1,3- propylene, B is 1,4-butylene, 1,5-pentylene, 1,6- hexylene or 1,5-pent-2-enylene, A is [di-lower alkylamino, lower alkyleneimino, morpholino, thiamorpholino or N-(lower alkyl, hydroxy-lower alkyl or lower alkanoyl-oxy-lower alkyl)-piperazino, wherein hydroxy or acetoxy is separated from the nitrogen by at least 2 carbon atomsl-lower alkyl or N-lower alkyl- (pyrrolidyl, pyrrolidylmethyl, piperidyl or piperidylmethyl), and R is hydrogen or hydroxy, or the ldehydro derivatives thereof, i.e. compounds of Formula IA A g0 Ph C B alk alkyl)piperazino, wherein the oxygen is separated from the nitrogen by at least 2 carbon atoms]-lower alkylidene, or N-lower alkyl-(pyrrolidylene, pyrrolidylmethylidene, piperidylene or piperidylmethylidene), or therapeutically useful acid addition salts of these compounds.

Especially valuable are compounds of Formulae II and III in which R is hydrogen or hydroxy, each of R R and R is hydrogen or one or two thereof are lower alkoxy, or one thereof is hydroxy, lower alkanoyloxy or halogen and the others are hydrogen, A is di-lower alkylamino-lower alkyl, l-lower alkyl-(piperidyl or piperidylmethyl), A is di-lower alkylamino-lower alkylidene, B is 1,4-butylene, 1,5-pentylene, 1,6- hexylene or 1,5-pent-2-enylene and m is the integer 1, 2 or 3, or therapeutically useful acid addition salts thereof.

Outstanding are those compounds of Formulae II and III and said therapeutically useful acid addition salts, in which R is hydrogen or hydroxy, each of R R and R is hydrogen or one or two thereof are methoxy or one thereof is hydroxy, acetoxy or chloro and the others are hydrogen, A is 3-(dimethylamino or diethylamino)- propyl or l-(methyl or ethyl)-3 or 4-(piperidyl or piperidylmethyl), A is 3-(dimethylamino or diethylamino)-propylidene, B is 1,4-butylene, 1,5- pentylene, 1,6-hexylene or 1,5-pent-2-enylene and m is the integer l, 2 or 3, especially the l-(3- dimethylamino-propylidene)-6-methoxy-1,2,3 ,4- tetrahydro-naphthalene-2-spirocyclopentane or therapeutically useful acid addition salts thereof, which show outstanding analgetic activity, for example, at a se. dose of about 150 mg/kg/day in the rabiit toothpulp test.

The compounds of the invention are prepared ac cording to methods known per se. For example, they are obtained by l. converting in a l-X-benzcycloalkane-Z- spiroaliphatic compound of the formula alk V wherein X is a substituent capable of being converted into A, X into said basic group or 2. reacting a l-oxo-benzcycloalkane-Z-spiroaliphatic compound of the formula with a tert. aminoalkyl or cycloalkyl metal compound and hydrolyzing the resulting adduct and, if desired, converting any resulting compound into another compound of the invention.

In the starting material shown under item 1) the substituent X is, for example, (a) a metallic group, e.g. an alkali metal, e.g. lithium, or halomagnesium, or (b) a reactively esterified hydroxy-alkyl or a phosphoniumalkyl group, such as a (halogeno, sulfonyloxy or a triarylphosphonium halide)-alkyl group, e.g. (chloro, bromo, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, tosyloxy, or triphenylphosphonium chloride)-alkyl or (c) a (nitro, oximino, imino, cyano,

carbamoyl, isocyanato or esterified carboxyamino, e.g. carbalkoxyamino)-alkyl, -alkenyl, -alkanoyl or -hydroxyalkyl group, an aminoalkenyl, -alkanoyl or -hydroxyalkyl group, cyano or preferably carbamoyl, e.g. COAm. The starting material corresponding to the X mentioned under item (a) is reacted with a reactively esterified, free or salified aminoalkanol or an unsubstituted or N-substituted ethyleneimine, that corresponding to the X mentioned under (b) is reacted with H-Am or an alkali metal or acyl, e.g. phthaloyl, derivative thereof, and that corresponding to the X mentioned under item (c) is reduced and/or hydrolyzed. In the condensation of the reactively modified alcohol with ammonia or amines according to (lb), said basic agents are preferably used in excess, in order to neutralize the generated acid. They may, however, also be used in equivalent amounts and in the presence of other condensing agents such as inorganic or organic bases, e.g. alkali metal carbonates or bicarbonates or tertiary nitrogen bases, for example tri-lower alkylamines, N,N-dimethylaniline or pyridine. The reduction of the nitro compounds, nitriles, amides, isocyanates, urethanes or alkanoyl compounds according to item (1c) is advantageously performed with the use of simply or complex light metal hydrides, such as boron hydride or alkali metal aluminum or borohydrides, e.g., lithium aluminum hydride or sodium borohydride. In this reduction, the cyano and carbamoyl groups are converted into aminomethyl groups, the isocyanato or esterified carboxyamino groups into methylamino groups and the alkanoyl groups into alkyl or whydroxy alkyl groups. Said oximes, Schiffs bases (i.e. iminoalkylor aminohydroxyalkyl compounds) or said w-amino-a-hydroxyalkyl reduction products of the alkanoyl compounds, as well as the nitro compounds and aminoalkenyl compounds, are preferably reduced with nascent hydrogen, such as hydrogen generated electrolytically or by the action of metals on acids or alcohols, e.g. zinc or iron and mineral or alkanoic acids, or with the use of catalytically activated hydrogen, e.g. hydrogen in the presence of nickel, platinum or palladium catalysts. lsocyanates and urethanes may also be subjected to hydrolysis, e.g. with the use of aqueous mineral acids or alkalies.

The metal compound mentioned under item (2) is preferably a Grignard compound, i.e. a halomagnesium, advantageously chloromagnesium compound, but also an alkali metal, e.g. lithium, compound. It is reacted with the oxo compound under the usual conditions, yielding, after hydrolysis with water or aqueous acid or ammonium salt solutions, compounds of the Formula I, in which R is hydroxy or, under dehydrating conditions, i.e. in strong acidic media, the l-dehydro derivatives thereof.

The compounds of the invention so obtained can be converted into each other according to known methods. For example, in resulting 1 -hydroxyor 1- dehydro-derivatives or compounds in which B contains a double bond, said hydroxy group and/or double bond can be eliminated reductively, for example with the use of catalytically activated hydrogen. A hydroxy group R may also be eliminated by dehydration, e.g. by pyrolysis or with the use of dehydration agents, e.g. acids, their halides or anhydrides, such as sulfuric acid, acetyl chloride or acetanhydride, to yield the l-dehydro derivatives. Compounds in which Am is a primary or secondary amino group, can be reacted with reactive esters of the corresponding alcohols, with lower alkyleneoxides, e.g. ethyleneoxide, or with aldehydes or ketones and reducing agents, e.g. formic acid, its functional derivatives or nascent hydrogen, in order to obtain secondary or tertiary amines, or quaternaries respectively. Resulting primary or secondary amines can also be acylated, for example, with a reactive functional derivative of a corresponding acid, such as a halide or anhydride thereof, or resulting acyl derivatives split, for example, with the use of acidic or alkaline hydrolyzing agents, or phthaloyl compounds with hydrazine, or reduced with simple or complex light metal hydrides. Resulting tertiary amines can be converted into N-oxides, for example by treating them with oxidation agents, such as hydrogen peroxide or peracids, e.g. aliphatic or aromatic percarboxylic acids. Furthermore, nitro groups may be introduced into aromatic moieties, e.g. by the action of nitric-sulfuric acid or by pyrolysis of nitrates, advantageously in acidic media, e.g. in trifluoroacetic acid, or nitro groups present therein reduced, e.g. with nascent hydrogen. Resulting hydroxycompounds, e.g. those of Formula I in which Ph or Am contains a hydroxy group, can be esterified and/or etherified, e.g. with the use of acid halides or anhydrides, including thionyl or phosphorus halides or oxyhalides, if desired, followed by the action of lower alkanols or alkali metal alkoxides. Resulting quaternaries can also be converted into tertiary amines, for example, from benzyl-quaternaries the benzyl residue can be split off by hydrogenation.

The compounds of the invention are obtained in the free form or in the form of their salts, depending on the conditions under which the process is carried out; the salts are also included in the present invention. Salts that are obtained can be converted into the free bases in known manner, for example, with alkalies or ion exchangers. Free bases that are obtained can be converted into salts by reaction with inorganic or organic acids, especially those that are suitable for the formation of therapeutically useful salts. Such acids are, for example, mineral acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, or perchloric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicyclic, 4- aminosalicylic, embonic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halogenbenzensulfonic, toluenesulfonic, naphthaenesulfonic, sulfanilic or cyclohexylsulfamic acid; methionine, tryptophane, lysine and arginine.

These or other salts of the invention, for example, the picrates, can also be used for purification of the bases obtained; the bases are converted into salts, the salts are separated and the bases are liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a free base is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

The invention further includes any variant of the present process, in which an intermediate product obtainable at any stage of the process is used as starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts. For example, the amines or alcohols mentioned above may be used in the form of their alkali metal, e.g. sodium or potassium salts. Mainly, those starting materials should be used in the process of the invention that lead to the formation of those compounds indicated above as being specially valuable.

The starting material used is known or, if new, may be prepared according to known methods. For example, that used in reaction (la) can be obtained by reduction of the l-oxo compound shown under item (2) with sodium borohydride, converting the resulting 1- hydroxy compound into a reactive ester thereof, e.g. with the use of thionyl or phosphorus halides, and reacting the l-halogeno compounds either with magnesium or alkali metals or their alloys. The starting material mentioned under items (lb) and (c) is prepared analogous to the method mentioned under item (2), e.g. by reacting an aliphatic metal or Grignard compound, e.g. that of the formula Mealk OCl-l -C H with the same oxo compound, subjecting the resulting adduct to hydrolysis and hydrogenation, in order to eliminate the benzyl group and, if desired, the l-hydroxy group formed also. In the resulting compounds, the l-hydroxyalkyl group can be modified according to methods known per se, for example reactively esterified, e.g. with strong mineral or sulfonic acids using, for example, thionyl halides or phosphorus halides or oxyhalides or sulfonyl halides, e.g. thionyl chloride, phosphorus trior pentabromide or oxychloride, tosyl or brosyl chloride, and resulting haloalkyl compounds reacted with phosphines, e.g. triphenylphosphine. The l-hydroxyalkyl compounds may also be oxidized, for example, with hydrogen peroxide or heavy metal salts or oxides, e.g. alkali metal chromates or permanganates, chromic or cupric salts, mercuric, manganese or silver oxide, in acidic or alkaline media respectively. Resulting acids may then be converted into their halides, e.g. with the above acid derivatives, which may further be reacted with amines, or resulting aldehydes are converted into oximes or Schiffs bases. The l-halogenoalkyl compounds can also be reacted with alkali metal cyanides or silver nitrite in order to obtain the l-cyano or nitro-alkyl starting material. Valuable intermediates in which X is formyl can be obtained from said ketones mentioned under item 2) by reaction with dimethylsulfoniummethylide or dimethyloxysulfoniummethylide (generated from the corresponding trimethylsulfonium salts) and rearranging the resulting spirooxiranes (epoxides) to the corresponding aldehydes by the action of Lewis acids, e.g. p-toluene sulfonic acid or boron trifluoride. Said aldehydes can either be reduced or oxidized to l-hydroxymethyl or l-carboxy compounds respectively, which may further be processed as shown above, or reacted with nitromethane or potassium cyanide in order to yield the corresponding 1-(2-nitroethenyl)-compounds or cyanhy drides respectively. Finally, the isocyanates and urethanes can be obtained from said acid halides and sodium azide and decomposing the resulting acid azide according to Curtius, i.e. by pyrolysis in the presence or absence of an alcohol, e.g. a lower alkanol. The starting material mentioned under item 2) can be obtained according to the methods described in Compt. Rend. 139, p. 1805 (1954), J. Org. Chem. 27, p. 3844 9 (1962), Bull. Soc. Chim. France 1957, p. 346 and 1966, p. 1693.

Starting materials or final products that are mixtures of isomers or racemates, can be separated into the single isomers or racemates by methods in themselves known, e.g. by fractional distillation, crystallization and/or chromatography. Racemic products can likewise be resolved into the optical antipodes, for example by separation of diastereomeric salts thereof, e.g. by the fractional crystallization of dor l-tartrates.

The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients suitable for either enteral, parenteral or topical application. Preferred are tablets and gelatin capsules comprising the active ingredient together with (a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, (b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol, for tablets also (c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired, ((1) disintegrants, e.g. starches, agar, alginic acid or its so dium salt, enzymes of the binders or effervescent mixtures and/or (e) adsorbents, colorants, flavors and sweeteners. lnjectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories or ointments are advantageously fatty emulsions or suspensions. They may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, sald for regulating the osmotic pressure and/or buffers. Said pharmaceutical compositions may also contain other therapeutically valuable substances. They are prepared according to conventional mixing, granulating or coating methods respectively and contain about 0.1 to 75 percent, preferably about 1 to 50 percent, of the active ingredient.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade, and all parts wherever given are parts by weight.

EXAMPLE 1 To the mixture of 2.3 g magnesium turnings, 20 ml tetrahydrofuran and 1 ml ethyl bromide (starter), the solution of 11.4 g 3-dimethylamino-propyl chloride in 20 ml tetrahydrofuran is added dropwise while stirring and keeping the mixture under nitrogen. After refluxing for 45 minutes, it is cooled in an ice bath and the solution of g l-oxo-l,2,3,4-tetrahydro-naphthalene- Z-spirocyclohexane in ml tetrahydrofuran is added dropwise while stirring and stirring is continued for 3 hours at room temperature. After standing overnight, the solution is decanted from some unreacted magnesium and evaporated in vacuo. The residue is taken up in 150 ml benzene and 75 ml water are added dropwise while stirring and cooling in an ice bath. The mixture is warmed up, the supernatant solution decanted from the gelatinous residue, which is triturated three times with 75 ml warm benzene, filtered off and washed with 150 ml warm benzene. The combined organic solutions are washed with water, dried, filtered and evaporated in vacuo. The residue is recrystallized from hexane, to

melting at 92.

It is dissolved in ml ethyl acetate, the solution acidified with hydrogen chloride in ethyl acetate, the precipitate formed filtered off and recrystallized from isopropanol, to yield the corresponding hydrochloride melting at 214 with decomposition.

The starting material can be prepared as follows: To the suspension of 57.2 g potassium t.-butoxide in 500 ml benzene, the solution of 29.8 g l-oxo-l,2,3,4- tetrahydro-naphthalene in 400 ml benzene is slowly added while cooling and stirring under nitrogen. Hereupon the solution of 46.9 g 1,5-dibromopentane in 50 ml benzene is added during 45 minutes and the mixture slowly heated and refluxed for 5 hours. After standing overnight at room temperature, it is poured over 350 g crushed ice and 80 ml concentrated hydrochloric acid. The organic layer is separated and the aqueous solution extracted with diethyl ether. The combined organic solutions are washed with 5 percent aqueous sodium carbonate and water, dried, filtered and evaporated in vacuo. The residue is distilled and the fraction boiling at 122128 /O.3 mm Hg collected; it represents the l-oxo-l,2,3,4-tetrahydro-naphthalene-2- spirocyclohexane.

EXAMPLE 2 To the Grignard reagent, prepared from 1.71 g magnesium, 0.5 ml ethyl bromide, 9.4 g 1-methyl-4-chloropiperidine and 50 ml tetrahydrofuran, the solution of 10 g l-oxo- 1 ,2,3 ,4-tetrahydro-naphthalene-Z- spirocyclohexane in 20 ml tetrahydrofuran is added dropwise while stirring and cooling. The mixture is stirred for 4 hours at room temperature, allowed to stand overnight and evaporated in vacuo. The residue is taken up in benzene and the solution of 25 ml glacial acetic acid in 25 ml water is added dropwise while cooling. The organic layer is separated and washed with water. To the combined aqueous solution 5 g ammonium chloride are added, followed by aqueous ammonia until it is basic. The mixture is extracted with diethyl ether, the extract washed with water, dried, filtered and evaporated in vacuo. The residue is recrystallized from aqueous methanol, to yield the l-hydroxyl-( l-methyl- 4-piperidyl)-l ,2,3,4-tetrahydro-naphthalene-2- spirocyclohexane of the formula melting at l37l 38.

3 g thereof are dissolved in 50 ml ethyl acetate and ml isopropanol and the solution is acidified with hydrogen chloride in ethyl acetate. The precipitate is filtered off and washed with ethyl acetate, to yield the corresponding hydrochloride melting at 225 with decomposition.

EXAMPLE 3 To the Grignard reagent prepared from 1.71 g magnesium, 10.3 g l-methyl-3-chloromethyl-piperidine, 0.5 ml ethyl bromide and 50 ml tetrahydrofuran, the solution of 10 g l-oxo-l,2,3,4-tetrahydro-naphthalene- 2-spirocyclohexane in ml tetrahydrofuran is added dropwise while cooling and stirring, and stirring is continued for 5 hours at room temperature. After standing overnight, the mixture is evaporated in vacuo, the residue taken up in benzene and the solution of ml glacial acetic acid in 25 ml water is added dropwise while stirring and cooling. The organic layer is separated, washed with water, the aqueous solutions combined and made basic with aqueous ammonia. The mixture is extracted with diethyl ether, the extract washed with water, dried, filtered and evaporated. The residue is recrystallized from aqueous methanol, to yield a solid fraction A and a mother liquor B. 2.4 g of the solid A are taken up in 75 ml hot ethyl acetate and isopropanol is added until dissolution occurs. The solution is then acidified with hydrogen chloride in ethyl acetate, the precipitate formed filtered off and washed with ethyl acetate-isopropanol, to yield the higher melting racemate (due to 2 assymetric carbon atoms) of the 1- hydroxyl l-methyl-3-piperidylmethyl 1 ,2,3,4- tetrahydro-naphthalene-2-spirocyclohexane hydrochloride of the formula HCl 2 N According to the method described in the previous examples, the following compounds of Formula II are The starting materials are prepared as follows: To the suspension of 57.2 g potassium t-butoxide in 500 ml benzene, the solution of 36 g l-oxo-6-methoxy- 1 ,2,3,4- tetrahydro-naphthalene in 150 ml benzene is added during 30 minutes while cooling and stirring under nitrogen. Hereupon, the solution of 46.9 g 1,5- dibromopentane in 100 ml benzene is added during 45 minutes, the mixture is allowed to slowly warm up to room temperature and is refluxed for 5 hours while stirring. After standing overnight, it is poured over 350 g crushed ice and 80 ml concentrated hydrochloric acid, the organic layer separated and the aqueous solution extracted with diethyl ether. The combined organic so lutions are washed with 5 percent aqueous sodium carbonate and water, dried, filtered and evaporated in vacuo. The residue is distilled and the fraction boiling at l-l63/0.3 mm Hg collected; it represents the loxo-o-methoxy-l ,2,3 ,4-tetrahydro-naphthalene-2- spirocyclohexane melting at 7 1 .5 after recrystallization from methanol.

In the analogous manner, the following starting materials are prepared from equivalent amounts of the corresponding intermediates;

a. l-oxo-S-methoxyl ,2,3,4-tetrahydro-naphthalene- 2-spirocyclohexane b.p. 138-l5l/0.2 mm Hg;

. 1-oxo-1,2,3 ,4-tetrahydro-naphthalene-2- spirocyclopentane, b.p. 99-lO3/0.2 mm Hg;

c. l-oxo-6-methoxy-l ,2,3,4-tetrahydro-naphthalene- 2-spirocyclopentane, b.p. l44l46/O.3 mm Hg; l-oxo-2,3-dihydro-indene-2-spirocyclohexane,

Another starting material is prepared as follows: To the stirred solution of 86 g butyrolactone and 1 kg chlorobenzene, kept under nitrogen, 500 g anhydrous aluminum chloride are added portionwise during 2 hours and the mixture is heated to for 20 hours. After cooling it is poured over 2.5 kg ice and 400 ml concentrated hydrochloric acid. The organic layer is separated and the aqueous solution extracted with toluene. The combined organic solutions are washed with water, 200 ml 20 percent aqueous potassium hydroxide and water again, dried, filtered and evaporated in vacuo. The residue is distilled and the fraction boiling at l l5/O.3 mm Hg collected. According to vapor phase chromatography, it consists of 46-48 percent 5-chloro-, 16-22 percent 6-chloroand 16-24 percent 7-chloro-l-oxo- 1,2,3,4-tetrahydro-naphthalene. On standing at room temperature for several days, crystals separate, which are filtered off and washed with cooled pentane to yield the mixture consisting of 56.4 percent S-chloroand 43.6 percent 7-chloro-1-oxol ,2,3,4-tetrahydronaphthalene (fraction A). The filtrate is allowed to stand for about 1 week, during which time another precipitate is formed. It is filtered off and washed with cooled pentane to yield the mixture consisting of 60.9 percent 5-chloro-, 2.9 percent 6-chloroand 33.7 perprepared: B =(CH cent 7-chloro-l-oxo-l,2,3,4-tetrahydro-naphthalene R R, R R A, m n Salt m.p.

OH H OCH; H do. 2 5 9395 OH H OCH; OCH;, do. 2 5 l 16-1 l7 OH Cl H H do. 2 5 HC! mixture OH H H Cl do. 2 5 HCl 20 l205 OH H H H do. 2 4 HCl 193 OH H OCH do. 2 4 7678 (fraction B). The solution of fraction A in pentane is subjected to thin layer chromatography on alumina and the eluate obtained from the faster moving band yields the S-chloro- 1 -oxo- 1 ,2,3,4-tetrahydro-naphthalene 14 CH- CH2- CH2- N( CH3 melting at 65.567. The eluate from the slower mov- 5 ing material yields the 7-chloro-l-oxol,2,3,4-tetrahy- HQ dro-naphthalene melting at 9899.5. melting at l74l75.

Fraction B S reacted as shown above, first with P It is taken up in hot ethyl acetate, and the solution 155mm trblltoXide and the resulting Potassium acidified with hydrogen chloride in ethyl acetate while pound with 1,5-dibr0m0pentarle I0 yi 10 cooling and stirring. The precipitate formed is filtered e. the mixture of S-chloroand 7-ChlOrO -O off and washed with ethyl acetate, to yield the correl,2,3,4-tetrahydro-naphthalene-Z- sponding hydrochloride melting at l72l74. spirocyclohexane, b.p. l30l40/0.2 mm Hg.

EXAMPLE 7 EXAMPLE 5 The hot solution of 2 g 1-hydroxy-l-(3- The mixture Of 7 g l-hy r yy rni dimethylamino-propyl)-6-methoxy-1,2,3,4-tetrahydropropyl)-6-methoxy-1,2,3,4-tetrahydro-naphthalene-Z- naphthalene-Z-spirocyclopentane (mp. 7678) in the spirocyclopentane (mp. 767 8), 30 m1 ChlOrOfOrm minimum amount of ethyl acetate is slowly acidified by and 5 ml acetyl chloride is refluxed for 70 minutes and the dropwise addition of hydrogen chloride in ethyl acevaporated in vacuo. The residue is taken up in water, etate while stirring. The precipitate formed after coolthe solution made basic with 2N aqueous sodium hying is filtered off and recrystallized from acetone to droxide and extracted with diethyl ether. The extract is yield the 1-(3-diethylamino-propylidene)-6-methoxywashed with water. dried, filtered and evaporated in l,2,3,4-tetrahydro-naphthalene-Z-spirocyclopentane vacuo. The residue is taken up in ethyl acetate, the sohydrochloride; it is identical with the compound oblution acidified with hydrogen chloride in ethyl acetate, tained according to Example 5. the precipitate formed filtered off and recrystallized from acetone to yield the l-(3-dimethylamino- EXAMPLE 8 propylidene)-6-methoxyl ,2,3,4-tetrahydro- According to the method described in Examples 5-7. naphthalene-Z-spirocyclopentane hydrochloride of the the following l-dehydro derivatives corresponding to f rmLfla Formula Ill are prepared: B =(CH- R R2 R3 A2 m n Salt m.p.

H H H =CH(CH 2 5 HC] l90l9l H OCH:I H do. 2 5 HCl l89l90 H OCH OCH;, do. 2 5 HCl l64l67 H H H do. 1 5 HO 211-212" Cl-I-CH -CH -N(CH H01 EXAMPLE 9 The mixture of 6.2 g l-(3-dimethylamino- CH O melting at l64-l65.

EXAMPLE 6 To the Grignard reagent prepared from 1.6 g magnesium, 8 g 3-dimethylaminopropyl chloride, 0.5 ml ethyl bromide and 50 ml tetrahydrofuran, the solution of 5 g 1-oxo-6-hydroxy-l ,2,3 ,4-tetrahydronaphthalene-Z-spirocyclohexane in 60 ml tetrahydrofuran is added dropwise while cooling and stirring, and stirring is continued for 3 hours at room temperature. After standing overnight, 75 ml water are added while cooling and stirring followed by 50 ml hot benzene. The organic solution is decanted off and hot benzene is added 3 more times. The combined organic solution is washed with water, dried, filtered and evaporated. The residue is recrystallized from chloroform-hexane to yield the 1-(3-dimethylamino-propylidene)-6- hydroxy-l ,2,3,4-tetrahydronaphthalene-2- spirocyclohexane of the formula It is dissolved in anhydrous diethyl ether and the solution neutralized with hydrogen chloride in ethyl acetate. The precipitate formed is filtered off and washed with diethyl ether, to yield the corresponding hydrochloride melting at l37l41.

EXAMPLE 10 To the mixture of 0.5 g lithium aluminum hydride and 25 ml anhydrous diethyl ether, the solution of 1.0 g 1-( N,N-dimethylcarbamoyl-ethyl )-6-methoxyl,2,3,4-tetrahydro-naphthalene-2-spirocyclohexane in 5 ml diethyl ether is added dropwise while stirring and the whole is stirred at room temperature overnight. Hereupon 1.5 ml ethyl acetate are added, followed by 0.5 ml water, 1 ml 5 percent aqueous sodium hydroxide and 1.5 ml water. The precipitate formed is filtered off, washed with diethyl ether, the filtrate dried and evaporated. The residue is dissolved in the minimum amount of diethyl ether, the solution neutralized with hydrogen chloride in ethyl acetate, the precipitate formed filtered off and washed with diethyl ether, to yield the 1- (3-dimethylamino-propyl)-6-methoxy-1,2,3,4- tetrahydro-naphthalene-2-spirocyclohexane hydrochloride melting at l36-139; it is identical with the product obtained according to Example 9.

The starting material is prepared as follows: To the Grignard reagent prepared from 1.7 g magnesium, 50 ml tetrahydrofuran and 1 1.9. g Z-benzyloxy-ethyl chloride, the solution of l l g l-oxo-6-methoxy-l,2,3,4- tetrahydro-naphthalene-2-spirocyclohexane in ml tetrahydrofuran is added dropwise while stirring and cooling. The mixture is stirred for 5 hours at room temperature and is allowed to stand overnight. It is again cooled in an ice bath, 30 ml water are added dropwise, followed by the mixture of 15 ml concentrated hydrochloric acid and 75 ml water, as well as by 100 ml diethyl ether. The organic layer is separated, the aqueous solution extracted with diethyl ether and the organic solutions combined. They are washed with water, dried, filtered and evaporated. 10 g of the residue is taken up in the minimum amount of hot glacial acetic acid, 3.5 g 10 percent palladium on charcoal are added and the mixture is hydrogenated at about -70 and 50 psi. until the theoretical amount of hydrogen has been absorbed. It is filtered, the filtrate evaporated in vacuo, the residue taken up in diethyl ether, the solution washed with 10 percent aqueous potassium carbonate, dried, filtered and evaporated, to yield the l- (2-hydroxy-ethyl )-6-methoxy-l ,2,3 ,4-tetrahydronaphthalene-2-spirocyclohexane.

To the mixture of 13.7 g thereof, 50 ml benzene and 4 g pyridine, the solution of 9 g thionyl chloride in 10 ml benzene is added while stirring and cooling. The mixture is refluxed until the evolution of sulfur dioxide ceases. After cooling, it is washed with water and 1 percent aqueous potassium carbonate, dried, filtered and evaporated, to yield the l-(2-chloro-ethyl)-6-methoxy- 1,2,3 ,4-tetrahydro-naphthalene-2-spirocyclohexane.

13 g thereof are added portionwise to the solution of 4 g potassium cyanide, 4 ml water and 16 ml ethanol at 80 while stirring. Hereupon the mixture is refluxed for 5 hours and evaporated in vacuo. The residue is taken up in water, the mixture extracted with ethyl acetate, the extract washed with water, dried, filtered and evaporated in vacuo, to yield the l-(2-cyano-ethyl)-6- methoxy-l ,2,3 ,4-tetrahydro-naphthalene-Z- spirocyclohexane.

The mixture of 11 g thereof, 12 ml water, 12 g sodium hydroxide and 40 ml ethylene glycol is refluxed for 4 hours and poured into 200 ml water. The solution obtained is acidified with concentrated hydrochloric acid and extracted with diethyl ether. The extract is washed with water, dried, filtered and evaporated. The residue is taken up in 10 ptrcent aqueous potassium carbonate, the mixture washed with diethyl ether and acidified with hydrochloric acid. It is again extracted with diethyl ether, the extract dried, filtered and evaporated, to yield the l-(2-carboxy-ethyl)-6-methoxyl,2,3,4-tetrahydro-naphthalene-Z-spirocyclohexane.

The mixture of 5.5 g thereof, 25 ml benzene and 2.5 ml thionyl chloride is refluxed for 1 hour and evaporated in vacuo. To the residue benzene is added, which again is distilled off. The residue is dissolved in 25 ml benzene, and the solution added dropwise to the mixture of 3.0 g dimethylamine in 25 ml benzene while stirring and keeping the temperature below 20. The mixture is stirred overnight at room temperature, and the precipitate formed filtered off. The filtrate is evaporated in vacuo, the residue taken up in diethyl ether, the solution washed with water, 2N aqueous hydrochloric acid, 2N aqueous sodium hydroxide and water, dried, filtered and evaporated, to yield the l-(N,N- dimethylcarbamoyl-ethyl)-6-methoxy-1 ,2,3 ,4- tetrahydro-naphthalene-2-spirocyclohexane, which is used as such without further purification.

The above-mentioned chloroethyl compound may be reacted with an excess of di-n-butylamine, pyrrolidine, morpholine or l-methyl-piperazine, in order to yield the l-(2-di-n-butylamino-, pyrrolidino-, morpholinoor N-methyl-piperazino-ethyl )-6-methoxy- 1 ,2,3 ,4- tetrahydro-naphthalene-2-spirocyclohexane.

The above-mentioned cyano compound may also be reduced as shown above for the dimethylamide, to yield the 1-(3-amino-propyl)-6-methoxy-1,2,3,4- tetrahydro-naphthalene-2-spirocyclohexane.

EXAMPLE 1 1 Preparation of 10,000 tablets each containing 100.0 mg or 50.0 mg of the active ingredient:

Formula A l-hydroxyl 3-dimethylamino-propyl 1,2,3,4-tetrahydro-naphthalene-Z- Procedure All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 65 ml water for A or 45 ml water for B and the suspension added to the boiling solution of the polyethylene glycol in 260 ml water for A or ml water for B. The paste formed is added to the powders which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35, broken on a screen with 1.2 mm openings and compressed into tablets using concave punches with 10.3 mm diameter for A or 7.1 mm diameter for B, uppers bisected.

In the analogous manner tablets are prepared, comprising a compound of the remaining examples as the active ingredient.

EXAMPLE 12 To the Grignard reagent, prepared from 2.1 l g magnesium, 0.5 ml ethylbromide and 10.6 g 3- dimethylamino-propyl chloride in 40 ml tetrahydrofuran, the solution of 9.9 g l-oxo-l,2,3,4-tetrahydronaphthalene2-spirocycloheptane in 20 ml tetrahydrofuran is added dropwise during 20 minutes while cooling, the mixture stirred for 3-hours at room temperature and allowed to stand overnight. It is decanted from unreacted magnesium, evaporated in vacuo and the residue taken up in 150 ml benzene. To the solution 75 ml water are added dropwise while stirring and cooling in an ice bath and the mixture warmed up at the steam cone. The organic layer is decanted off and the gelati nous residue extracted 3 times with 75 ml hot benzene while stirring. It is finally filtered off, washed with 150 ml hot benzene, the combined organic solutions washed with water, dried and evaporated. The residue is taken up in 75 ml ethyl acetate and the solution strongly acidified with hydrogen chloride in ethyl acetate. The precipitate formed is filtered off, washed with ethyl acetate and recrystallized from isopropanol, to yield the l-hydroxy-l-(3-dimethylamino-propyl)- 1,2,3 ,4-tetrahydro-naphthalene-2-spirocycloheptane hydrochloride of the formula.

(CH2) N(CH3)2 .l-lCl hydromelting at l88-l89 after recrystallization from acctone.

EXAMPLE 13 To the Grignard reagent. prepared from 1.49 g magnesium, 0.5 ml ethylbromidc, 7.46 g 3'dimethylaminopropyl chloride and 40 ml tetrahydrofuran, the solution of 7 g l-oxo-4-benzosuberane-2-spirocyclohexane in 20 ml tetrahydrofuran is added dropwise while stirring and cooling. After standing overnight at room temperature, the solution is decanted off and evaporated in vacuo. The residue is taken up in benzene, to the solution 60 ml water are added dropwise while cooling and stirring and the mixture warmed up in hot water. The organic solution is decanted off, the residue triturated with warm benzene and the combined organic solutions washed with water, dried, filtered and evaporated. The residue is taken up in 200 ml ethyl acetate and the solution acidified with hydrogen chloride in ethyl acetate. The precipitate formed is filtered off and recrystallized from isopropanol, to yield the l-hydroxy-l-(3- dimethylamino-propyl)-benzosuberane-2- spirocyclohexane hydrochloride of the formula (on N(CH .HCl HO 2 3 3 2 melting at 258 with decomposition.

EXAMPLE 14 To the Grignard reagent, prepared from 2.22 g magnesium, 0.5 ml ethyl bromide and l 1.1 g 3- dimethylamino-propyl chloride in 40 ml tetrahydrofuran, the solution of 9.7 g 1-oxo-1,2,3,4- tetrahydronaphthalene-2-spirocycl0-3-hexene in 20 ml tetrahydrofuran is added dropwise while stirring and cooling. The mixture is stirred for 5 hours at room temperature and allowed to stand overnight. The supernatant solution is decanted off, evaporated in vacuo, the residue taken up in 100 ml benzene and to the solution 50 ml water are added dropwise while stirring and'cooling. The mixture is heated at the steam cone, the organic layer separated and the residue triturated 3 times with ml hot benzene and finally washed with ml benzene. The combined solutions are washed with water, dried, filtered, evaporated and the residue recrystallized from hexane, to yield the l-hydroxy-l-(3- dimethylamino-propyl l ,2,3 ,4- tetrahydronaphthalene-2-spirocyclo-3-hexene of the formula melting at 9395. The corresponding hydrochloride melts at 203-205 with decomposition.

EXAMPLE l5 The solution of 4 g l-hydroxy-l-(3-dimethylaminopropyl) l,2,3.4-tetrahydro-naphthalene 2-spirocyclo- 3-hcxene in 50 ml chloroform and 3.35 ml acetyl chloride is refluxed for 70 minutes and evaporated in vacuo. The residue is taken up in water, the solution strongly acidified with concentrated hydrochloric acid and washed with diethyl ether. The aqueous .solution is made basic with 6 N aqueous sodium hydroxide, extracted with diethyl ether, the extract washed with water, dried and evaporated. The residue is taken up in ethyl acetate, the solution acidified with hydrogen chloride in ethyl acetate, the precipitate formed filtered off and washed with ethyl acetate, to yield the 1- (3-dimethylaminopropylidene)-1,2,3 ,4-tetrahydronaphthalene-2-spirocyclo-3-hexene hydrochloride of the formula melting at 197 with decomposition.

EXAMPLE 16 The mixture of 42 g 1,6-dihydroxy-1-(3- dimethylaminopropyl l ,2,3 ,4-tetrahydronaphthalene-2-spirocyclohexane, 250 ml chloroform and 38 ml acetyl chloride is heated at the steam cone for 70 minutes and evaporated in vacuo. The residue is taken up in water, the solution washed with diethyl ether and the aqueous layer made basic with 2N aqueous sodium hydroxide. It is extracted 3 times with diethyl ether, the extract washed with water, dried and evaporated. The residue is taken up in ethyl acetate, the solution acidified with hydrogen chloride in ethyl acetate, the precipitate formed filtered off and recrystallized from isopropanolethyl acetate, to yield the 1- (3-dimethylamino-propylidene )-6-acetoxyl ,2,3 ,4- tetrahydro-naphthalene-2-spirocyclohexane hydrochloride of the formula CH-CH -CH N( CH 2 HCl melting at 188-189.

EXAMPLE 17 To the Grignard reagent prepared from 1.71 g magnesium, 10.3 g l-methyl-3-chloromethyl-piperidine, 0.5 ml ethyl bromide and 50 ml tetrahydrofuran, the solution of 1 1.6 g l-oxo-6-methoxy-1,2,3,4-tetrahydronaphthalene-2-spirocyclopentane in 20 ml tetrahydrofuran is added dropwise while cooling and stirring, and stirring is continued for 5 hours at room temperature. After standing overnight. the mixture is evaporated in vacuo, the residue taken up in benzene and the solution of ml glacial acetic acid in 25 ml water is added dropwise while stirring and cooling. The organic layer is separated, washed with water, the aqueous solutions combined and made basic with aqueous ammonia. The

mixture is extracted with diethyl ether, the extract washed with water, dried, filtered and evaporated. The residue is taken up in ml ethyl acetate, the solution acidified with hydrogen chloride in ethyl acetate and the precipitate formed filtered off. It is several times triturated with warm acetone, to yield the l-hydroxy-ll-methyl-3-piperidylmethyl)-6-methoxy-1,2,3 ,4-

tetrahydro-naphthalene-2-spirocyclopentane hydrochloride of the formula CH 1 H01 melting at 219 with decomposition.

The acetone solution is evaporated in vacuo, the residue combined with that obtained from the ethyl acetate filtrate, and taken up in water. The solution is washed CH'" COOH l C l H3 cit-coon O CH- melting at l44l46.

EXAMPLE 18 To the Grignard reagent prepared from 12.7 g magnesium and 63.5 g 3-dimethylamino-propyl chloride in 400 ml tetrahydrofuran, the solution of 40 g l-oxo-6- hydroxy-l ,2,3 ,4-tetrahydro-naphthalene-2- spiroeyclohexane in 200 ml tetrahydrofuran is added dropwise while cooling and stirring, and stirring is continued for 5 hours at room temperature. After standing overnight, 200 ml water are added while cooling, followed by 200 ml benzene. The organic solution is decanted off and the residue is triturated 3 more times with benzene. The combined organic solutions are washed with water, dried. filtered and evaporated in vacuo. The residue is taken up in'tlie minimum amount of isopropanol and the solution diluted with about the same volume hexane, to yield the 1,6-dihydroxy-l-(3- dimethylamino-propyl 1 ,2,3,4-tetrahydronaphthalen-Z-spirocyclohexane of the formula HO (CH2)3-N(CH3)2 melting at 1()8l Under these mild conditions (avoiding hot benzene as well as acidic chloroform and evaporating in vacuo). dehydration does not occur, as is the case in Examples 6, 12 and 17.

EXAMPLE 19 Through the solution of 3.5 g dimethylaminopropylidene)-6-methoxy- 1 ,2,3,4- tetrahydro-naphthalenc-2-spirocyclopentane in 35 ml ethanol. methyl bromide is bubbled for minutes while stirring at room temperature, and the mixture is allowed to stand for 2 /2 days. It is evaporated in vacuo, the residue triturated with diethyl ether and recrystallized from isopropanol, to yield the 1-(3- trimethylammonium-propylidene)-6methoxy-1,2,3,4- tetrahydro-Z-spirocyclopentane bromide of the formula CH -CH CHO melting at 223-224.

EXAMPLE 20 The solution of 3 g l-(2-nitro-ethenyl)-1,2,3,4- tetrahydro-naphthalene-Z-spirocyclopentane in 15 ml tetrahydrofuran is added dropwise to the stirred mixture of 0.7 g lithium aluminum hydride in 17 ml diethyl ether. After refluxing the mixture for 6 hours, it is cooled and 0.7 ml water, 1.4 ml 12 percent aqueous sodium hydroxide and 2.1 ml water are added in this sequence. It is filtered, the filtrate washed with water, dried, evaporated and the residue taken up in ethyl acetate. The solution is acidified with hydrogen chloride in ethyl acetate, the precipitate formed filtered off and recrystallized from acetone, to yield the l-(2- aminoethyl l ,2.3 ,4-tetrahydro-naphthalene-Z- spirocyclopentane hydrochloride of the formula H HCl showing in the IR. spectrum inter alia bands at 750, 1250. 1600 and 2500 cm.

The starting material is prepared as follows: The mix ture of 2.4 g sodium hydride and 80 ml dimethylsulfoxide is heated to under nitrogen until the evolution of hydrogen ceases. It is cooled to room temperature, diluted with ml tetrahydrofuran and rapidly combined with the solution of 20.4 g trimethylsulfoniumiodide in 80 ml dimethylsulfoxide while stirring at 5 to -10. Hereupon the solution of 20 g l-oxol,2,3,4-tetrahydronaphthalene2-spirocyclopentane in 20 ml tetrahydrofuran is added during 10 minutes while stirring at said temperature. After 15 minutes, the mixture is stirred for 45 minutes at room temperature. It is combined with 800 ml water, extracted with diethyl ether, the extract washed with water, dried and evaporated in vacuo, to yield the l,2,3,4-tetrahydronaphthalene-1-spirooxirane-2-spirocyclopentane.

10.7 g of said epoxide is added to the azeotropically dried solution of 2.0 g p-toluene sulfonic acid in 200 ml benzene, and the whole is refluxed for 16 hours. After cooling, it is washed with aqueous potassium carbonate and water, dried, filtered and evaporated in vacuo, to yield the l,2,3,4-tetrahydro-naphthalene-Z- spirocyclopentane- 1 -carboxaldehyde.

To the mixture of 5.3 g thereof, 1.6 g nitromethane and 30 ml methanol, 4.6 ml N n aqueous sodium hydroxide are added dropwise while stirring and cooling in an ice bath. After stirring for 3 hours at 2025, the mixture is strongly acidified with 6N hydrochloric acid while cooling and diluted with water. The precipitate formed is filtered off and washed with water, to yield the 1-(2-nitroethenyl)-l,2,3,4-tetrahydro-naphthalene- 2-spirocyclopentane.

EXAMPLE 21 According to the method described in Example 3, the 1-hydroxy-l-( 1-methyl-3-piperidylmethyl)-1,2,3,4- tetrahydro-naphthalene 2-spirocyclopentane hydrochloride, m.p. 214 (dee.) and, according to Example 9, the l-(3-dimethylaminopropyl)-6-methoxy-1,2,3,4- tetrahydro-naphthalene-2-spiroeyclopentane hydrochloride, m.p. l74l 76, are prepared from equivalent amounts of the corresponding starting material.

EXAMPLE 22 tetrahydronaphthalene-Z-spirocyclopenta'ne hydrochloride of the formula CH- CH N(CH HCl CH O showing in the IR. spectrum strong bands at 1032, 1246, 1315, 1502 and 1606 cm".

The starting material is prepared as follows: To the suspension of 6 g magnesium, 1 crystal iodine and 50 ml tetrahydrofuran, 15 ml of a solution, prepared from 33 g freshly distilled vinyl bromide and 50 ml tetrahydrofuran, are added dropwise at 30, and the remainder of the solution added during 20 minutes at 45. The mixture is refluxed for 30 minutes, cooled to 20 and diluted with 20 ml diethyl ether. Hereupon the solution of 18 g l-oxo-6-methoxyl ,2,3,4- tetrahydronaphthalene-2-spirocyclopentane in 15 ml tetrahydrofuran and 100 ml diethyl ether is added at 1 5, and stirring is continued for 3 hours at this temperature. The mixture is allowed to stand overnight at room temperature, refluxed for 2 hours, cooled and poured onto ice and saturated aqueous ammonium chloride. The organic layer is separated, washed with water, dried, filtered and evaporated, to yield the lhydroxy-l-vinyl-6methoxy-l,2,3,4- tetrahydronaphthalene-2-spirocyclopentane.

The solution of 6.5 g thereof in 70 ml chloroform and 2 ml pyridine is added dropwise to the mixture of 2.75 g phosphorus tribromide and 50 ml chloroform while stirring at 50. The mixture is stirred at said temperature for 3 hours and allowed to warm up to room temperature overnight. It is washed with 2N hydrochloric acid, water and aqueous sodium bicarbonate, dried, filtered and evaporated, to yield the l-(2- bromoethylidene )-6-methoxy-l ,2,3 ,4- tetrahydronaphthalene-Z-spirocyclopentane.

EXAMPLE 23 The mixture of 10 g of l-(2-chloroethyl)-6-methoxy- 1,2,3 ,4-tetrahydronaphthalene-Z-spirocyclohexane, (prepared in Example 10), 6.75 g of tri-nbutylphosphine and 75 ml of 1,2-dimethoxyethane isv refluxed for 24 hours. The reaction mixture is evaporated under reduced pressure to yield the crude 6- methoxy-1,2,3 ,4-tetrahydronaphthalene-2 spirocyclohexyl-l-ethyl-tri-n-butyl phosphonium chloride.

The mixture of 16 g thereof, 8 g of dimethylamine and 50 ml of ethanol is heated in an autoclave to 100 for 18 hours, cooled and evaporated to remove excess dimethylamine. The reaction mixture is diluted with water, made basic with 2N aqueous sodium hydroxide and extracted with diethyl ether. The extract is washed with water, dried and evaported. The residue is distilled under reduced pressure and the fraction boiling between l58l63 at 0.3 mm Hg is collected and is the 1-( Z-dimethylaminoethyl)-6-methoxy-l ,2,3.4- tetrahydronaphthalene-Z-spirocyclohexane of the formula CH -CH N CH5 EXAMPLE 24 The solution of 5.4 g of 1.2.3.4-

24 tetrahydronaphthalene-2-spirocyclopentane-lcarboxaldehyde (prepared in Example 20), 6 g of methylamine and 50 ml of ethanol is heated in a sealed tube to 60 for 18 hours. After cooling, 2.5 g of sodium borohydride is added slowly with stirring and the reaction mixture allowed to stand at room temperature overnight. It is then evaporated under reduced pressure to remove excess methylamine; the residue is diluted with water and extracted with ethyl acetate. The extract is dried and evaporated under reduced pressure. The residue is taken up in ethyl acetate and treated with anhydrous hydrogen chloride in ethyl acetate to afford the l-methylaminomethyl-l ,2,3 ,4- tetrahydronaphthalene-2-spirocyclopentane hydrochloride of the formula CHNHCI-l HCl and characterized by bands between 2650 and 2400 cm and at 760 cm in its infrared spectrum.

EXAMPLE 25 To the solution of 7 g of l-(2-cyanoethyl)6- methoxy-l,2,3,4-tetrahydronaphthalene in 50 ml of tetrahydrofuran are added 30 ml of a 1 molar solution of diborane in tetrahydrofuran. The resulting mixture is stirred for 3 hours, allowed to stand overnight and decomposed by the dropwise addition of 10 ml of ethanol. The mixture is then treated with the solution of hydrogen chloride in ethylacetate, to yield the 1-(3- aminopropyl)-6-methoxy-1,2,3,4- tetrahydronaphthalene-Z-spirocyclohexane hydrochloride of the formula HCl CH O and showing characteristic infrared absorption bands at 1608, l258and 810 cm".

EXAMPLE 26 To the solution of 3.5 g of dimethylaminopropylidene )-6-methoxyl 2,3,4- tetrahydronaphthalene-l-spirocyclopentane (obtained from its hydrochloride in Example 5) in 15 ml of chloroform is added the solution of 2.44 g of mchloroperbenzoic 'acid in 25 ml of chloroform over 25 minutes at room temperature. The resulting mixture is allowed to stir at room temperature for one hour, diluted with 40 ml of chloroform and washed with aqueous sodium carbonate and water. The chloroform solution is dried and evaporated under reduced pressure. The residue is taken up in diethyl ether and crystallized to give the l-(3-dimethylaminopropylidenc)-6- melting at 92.

, EXAMPLE 27 To the Grignard reagent, prepared from 3,45 g magnesium, 0.5 ml ethyl bromide and 22.5 g 3 diethylaminopropyl chloride in 50 ml tetrahydrofuran, the solution of 23.2 g l-oxo--methoxy-l,2,3,4- tetrahydro'naphthaIene-Z-spirocyclopentane in 30 ml tetrahydrofuran is added dropwise while cooling and stirring. After 4 hours stirring at room temperature and allowing to stand overnight, the mixture is cooled in an ice bath and 25 ml water are added dropwise, followed by 50 ml water. The mixture is heated on a steam bath, the supernatant solution decanted off and the gelatinous residue triturated 3 times with lOO ml hot benzene. The combined organic solutions are washed with water, filtered and evaporated under reduced pressure. The residue is recrystallized first from hexane and then from hexane-diethyl ether, to yield the l-hydroxy-l-( 3- diethylaminopropyl )-6-methoxyl ,2,3 ,4- tetrahydronaphthalene-2-spirocyclopentane of the formula melting at 8486.

The mixture of g thereof. 6.2 ml acetyl chloride and 50 ml chloroform is refluxed for 1 hour and evaporated under reduced pressure. The residue is recrystalized twice from acetone, to yield the l-(3- diethylaminopropylidene )-6-methoxyl ,2,3,4- tetrahydronaphthalene-2spirocyclopcntane hydrochloride, melting at l57-l59.

EXAMPLE Z8 due is triturated with hot benzene, the combined organic solutions washed with water, dried, evaporated under reduced pressure and the residue recrystallized from hexane, to yield the l-hydroxy-1-(3- dimethylaminopropyl)-7-methoxyl ,2,3 ,4- tetrahydronaphthalene-2-spirocyclopentane of the formula HO (CH2)3-N(CH3)2 CH O melting at -77.

The mixture of) g thereof, 6.1 ml acetyl chloride and 50 ml chloroform is refluxed for 1 /2 hours and evaporated under reduced pressure. The residue is triturated with diethyl ether and recrystallized from acetoneisopropanol, to yield the l 3- dimethylaminopropylidene )-7-methoxy-l ,2,3 ,4- tetrahydronaphthalene-2-spirocyclopentane chloride, melting at 183l85.

The starting material is prepared as follows: To the suspension of 54.8 g potassium t. butoxide in 250 ml benzene, the solution of l-oxo-7-methoxy-l,2,3,4-tetrahydronaphthalene in 100 ml benzene are added during 10 minutes while cooling and stirring under nitro gen. The mixture is diluted with 100 ml benzene and stirred for 10 minutes more at about 15. Thereupon the solution of 42.2 g 1,4-dibromobutane in 50 ml benzene is added during 30 minutes, and the mixture refluxed for 7 hours. After stirring overnight at room temperature, it is poured onto ice and ml concentrated hydrochloric acid. The aqueous layer is ex tracted with diethyl ether and the combined organic solution washed with 5 percent aqueous sodium carbonate and water. It is evaporated under reduced pressure, the residue distilled through a reflux column and the fraction boiling at l25-l35/0.2 mml-lg collected, to yield the 1-oxo-7-methoxy-l ,2,3 ,4- tetrahydronaphthalene-2-spirocyclopentane.

EXAMPLE 29 To the mixture of 14.6 g magnesium and 50 ml tetrahydrofuran, the solution of 73 g 3- dimethylaminopropyl chloride in lOO ml tetrahydrofuran is added dropwise, once the reaction has started with the first 40 ml thereof. It is stirred, cooled and f1- nally refluxed for 45 minutes. Hereupon the solution of 70 g l-oxo-o-methoxy-l,2,3,4-tetrahydronaphthalene- 2-spirocyclopentane in ml tetrahydrofuran is added dropwise during 50 minutes while stirring and cooling in an ice bath. The mixture is stirred for 4 hours at room temperature and allowed to stand overnight. It is decanted from unreacted magnesium and evaporated under reduced pressure. The residue is taken up in the minimum amount of benzene and ml water are added dropwise while stirring and cooling with an ice bath. Hereupon the mixture is heated at the steam cone, the hot solution decanted from the residual gel and filtered. The residue is washed with 150 ml hot benzene, the filtrate washed with water, dried, filtered, evaporated and the residue recrystallized from hexane, to yield the l-hydroxy-l-(3-dimethylaminopropyl)-6- hydromethoxyl ,2,3 ,4-tetrahydronaphthalene2- spirocyclopentane, melting at 7880; it is identical with the compound described in Example 4.

The mixture of 60 g thereof, 41 ml acetyl chloride and 300 ml chloroform is refluxed on the steam bath for 80 minutes and evaporated under reduced pressure. The residue is taken up in water, the mixture made basic with 2N aqueous sodium hydroxide and extracted with diethyl ether. The extract is washed with water, dried, filtered and evaporated under reduced pressure. The residue is taken up in the minimum amount of ethyl acetate, the solution strongly acidified with hydrogen chloride in ethyl acetate, the precipitate formed filtered off, washed with ethyl acetate and recrystallized from about 600 ml acetone, to yield the l-(3- dimethylaminopropylidene)-6-methoxy-l ,2,3,4- tetrahydronaphthalene-Z-spiroeyclopentane hydrochloride melting at 164-166; it is identical with the product obtained according to Example 5.

The starting material is prepared as follows: To the mixture of l7l g potassium t. butoxide and 750 ml benzene, the solution of 107 g 1-oxo-6-methoxy-l,2,3,4- tetrahydronaphthalene in 350 ml benzene is added during 15 minutes while stirring. The mixture is diluted with 150 ml benzene, stirred for minutes at and the solution of 131 g 1,4-dibromobutane in 100 ml benzene is added during 35 minutes while stirring and cooling in an ice bath. The mixture is slowly heated, diluted with another 450 ml benzene, refluxed for 6 hours, stirred for an additional 2 hours and allowed to stand overnight at room temperature. It is poured onto ice and 240 ml concentrated hydrochloric acid, the organic layer separated and the aqueous solution extracted with 250 ml diethyl ether. The combined organic solutions are washed with water, 100 ml 5 percent aqueous sodium carbonate and water, dried, filtered, evaporated under reduced pressure, the residue distilled and the fraction boiling at 137l40/0.2 mm Hg collected, to yield the l-oxo-6-methoxy-l,2,3,4- tetrahydronaphthalene-2-spirocyclopentane; it is identical with that described in Example 4.

EXAMPLE 30 To the solution of 3.37 g dimethylaminopropylidene)-6-methoxyl1,23,4- tetrahydronaphthalene-2-spirocyclopentane hydrochloride in 30 ml water, 0.9 ml 50 percent aqueous sodium hydroxide are added and the mixture extracted with 40 ml toluene. The extract is dried, filtered and evaporated under reduced pressure. The residue is taken up in 9 ml 2-propanol and the pH thereof adjusted to 4 by the addition of about 7.3 ml of the solution prepared from 1.3 g maleic acid and 9 ml propanol. The mixture is slowly cooled to 5 and stirred overnight. It is filtered, the residue dissolved in 18 ml boiling 2-propanol and the solution again stirred at 5 overnight. It is filtered and the residue washed with 5 ml cold 2-propanol, to yield the l-(-3- dimethylaminopropylidene )-6-methoxy- 1 ,2,3,4- tetrahydronaphthalene-Z-spirocyclopentane. malcate, melting at l22-l24.

EXAMPLE 31 Preparation of l0,000 tablets, each containing 75 mg of the active ingredient:

Formula: I-( 3dimethylaminopropylidene )6- methoxyl .2,3.4-tctrahydronaphthalene-Z-spirocyclopentanc malcale 750.0 g Lactose l222$ g Corn starch 495.0 g Magnesium aluminum silicate 90.0 g Methyl cellulose cps) 60.0 g Colloidal silica 30.0 g Stearic acid 30.0 g Magnesium stearate 22.5 g Anhydrous ethanol q.s

Purified water q.s.

Procedure All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, lactose, starch, magnesium aluminum silicate, methyl cellulose and half of the silica are mixed in a suitable mixer. Then the 50 percent aqueous ethanol is added to the powders, which are granulated and the granulate dried overnight. It is broken on a screen with 1.2 mm open ings, mixed with the remaining silica, magnesium stearate and stearic acid and compressed into tablets, using concave punches with 10.3 mm diameter, uppers bisected.

What is claimed is:

l. A l-basically substituted benzcycloalkane-Z- spiroaliphatic compound of the formula in which Ph is 1,2-phenylene, or 1,2-phenylene substituted by up to two members selected from the group of lower alkyl, hydroxy, lower alkoxy, halogeno, trifluoromethyl or nitro, alk is lower alkylene contributing l to 3 ring-carbon atoms, B is lower alkylene or alkenylene contributing 4 to 6 ring-carbon atoms, A is amino, monoor di-lower alkylamino, N-(hydroxyl-lower alkyl)-N-lower alkylamino, di-(hydroxy-lower alkyl)- amino in which hydroxy is separated from amino by at least 2 carbon atoms, monocyclic, 3 to 7 ringmembered lower cycloalkylamino, cycloalkyl-lower alkylamino, N-cycloalkyl-N-lower alkylamino or N- cycloalkyl-lower alkyl-N-lower alkylamino, HPh-lower alkylamino, or N-lower alkyl-HPh-lower alkylaminolower alkyl and R is hydrogen or hydroxy, or the N- oxide or therapeutically useful acid addition salts thereof.

2. A compound as claimed in claim 1, in which formula Ph is LZ-phenylenc, (lower alkyl)-l.2-phenylene. (hydroxy-l.Z-phenylene, monoor di-(lower alkoxy)- 1,2-phenylene, (halogeno )-l ,Z-phenylene or (trifluoromcthyl)-1.2-phenylene, alk is methylene, l,2-ethylene or l,3propylene, B is 1,4-butylene. 1,5-pentylene, 1,6- hexylenc or l.5-pent-2-enylene, A is di-lower alkylamino. lower alkyl. and R is hydrogen or hydroxy, or therapeutically useful acid addition salts thereof.

3. A compound as claimed in claim 1 and having the formula 29 R A R,

in which R is hydrogen or hydroxy, each of R R and R is hydrogen or one or two thereof are lower alkoxy, or one thereof is hydroxy or halogen and the others are hydrogen, A is di-lower alkylamino-lower alkyl, B is 1,4-butylene, 1,5-pentylene, 1,6-hexylene or 1,5-pent- 2-enylene and m is the integer l, 2 or 3, or therapeutically useful acid addition salts thereof.

4. A compound as claimed in claim 3, in which formula R is hydrogen or hydroxy, each of R R and R is hydrogen or one or two thereof are methoxy or one thereof is hydroxy or chloro and the others are hydro gen, A is B-(dimethylamino or diethylamino)-propyl, B is l.4-butylene, 1,5-pentylene, l,6-hexylene or 1,5- pent-Z-enylene and m is the integer 1, 2 or 3, or therapeutically useful acid addition salts thereof.

5. A compound as claimed in claim 4 and being the l-hydroxyl 3-dimethylamino-propyl benzosuberane-2-spirocyclohexane or a therapeutically useful acid addition salt thereof. 

1. A 1-BASICALLY SUBSTITUTED BENZCYCLOALKANE-2SPIROALIPHATIC COMPOUND OF THE FORMULA
 2. A compound as claimed in claim 1, in which formula Ph is 1,2-phenylene, (lower alkyl)-1,2-phenylene, (hydroxy-1,2-phenylene, mono- or di-(lower alkoxy)-1,2-phenylene, (halogeno)-1,2-phenylene or (trifluoromethyl)-1,2-phenylene, alk1 is methylene, 1,2-ethylene or 1,3-propylene, B is 1,4-butylene, 1,5-pentylene, 1,6-hexylene or 1,5-pent-2-enylene, A is di-lower alkylamino, lower alkyl, and R is hydrogen or hydroxy, or therapeutically useful acid addition salts thereof.
 3. A compound as claimed in claim 1 and having the formula
 4. A compound as claimed in claim 3, in which formula R is hydrogen or hydroxy, each of R1, R2 and R3 is hydrogen or one or two thereof are methoxy or one thereof is hydroxy or chloro and the others are hydrogen, A1 is 3-(dimethylamino or diethylamino)-propyl, B1 is 1,4-butylene, 1,5-pentylene, 1,6-hexylene or 1,5-pent-2-enylene and m is the integer 1, 2 or 3, or therapeutically useful acid addition salts thereof.
 5. A compound as claimed in claim 4 and being the 1-hydroxy-1-(3-dimethylamino-propyl)-benzosuberane-2-spirocyclohexane or a therapeutically useful acid addition salt thereof. 